Neuropathic pain (NP) is caused by a primary lesion of the nociceptive pathway. Hyperexcitability of this pathway resulting from peripheral and central sensitization is believed to be the neurophysiological hallmark of NP. Correspondingly, the standard paradigm of pharmacological management of NP is to suppress this hyperexcitability, as exemplified by the clinical use of certain antiepileptic drugs for the treatment of NP. However, the frequent refractoriness of NP to these drugs suggests that neuronal hyperexcitability should be approached differently. Because the pathophysiological process in NP exhibits a transition from an initial loss of afferent input to subsequent hyperexcitability and eventual paroxysmal discharges, it may be regarded as a functional compensatory response of the nervous system, similar to homeostatic regulation of neuronal activity. Therefore, we hypothesize that the hyperexcitability underlying NP results from excessive homeostatic compensation to the initial loss of activity and that stimulating neuronal activity will suppress this overcompensation and control NP. This hypothesis is supported by our preliminary data showing that enhancing cortical neuronal activity by either ontogenetic stimulation or focal drug release is effective in controlling pain in animal models of NP. In this project, we will employ a well-established transient spinal cord ischemia model of NP in mice to determine whether controlled ontogenetic stimulation of specific populations of cortical neurons or pharmacological enhancement of cortical activity will prevent this progression and control NP, and whether injury of the nervous system will induce pathological homeostatic regulation, which progresses to cortical hyperexcitability. The direct effect and mechanism of ontogenetic stimulation on neuronal hyperexcitability will be further determined. The success of this project will establish the role of excessive homeostatic compensation in the development of NP and will verify a novel strategy for controlling NP by stimulating neuronal activity. Establishing this nove strategy not only will provide a theoretical basis for the current use of cortical stimulation for P (e.g., repetitive transcranial magnetic stimulation), but also will open a door for discovering new drugs for controlling NP by promoting neuronal activity. Because of its unconventional concept, innovative approach, and significant relevance to public health, this proposal is particularly suited to the EUREKA mechanism.